1. Field of the Invention
This invention relates to biopharmaceutical product cryogenic preservation methods and apparatus, more particularly this invention relates to biopharmaceutical product cryogenic preservation using a cryopreservation vial apparatus and methods.
2. Description of Related Art
Cryopreservation and cryoprocessing of biopharmaceutical products is important in the manufacturing, use, and sale of these products. However, in order to process many of these products, the cryopreservation or cryoprocessing must be done uniformly and in a controlled manner or the quality and value of the product may be lost. For example, when processing cells for cryopreservation, if the cells are frozen too quickly with too high of a water content, then the cells can develop intracellular ice crystals. As a result, the cells may will rupture and/or become unviable. Another example is the freezing of protein solutions that are formulated for pharmaceutical use. Ideally, freezing of these solutions is uniform throughout the frozen volume. Uniformity of the frozen volume tends to provide, throughout the frozen volume, similar concentrations of solutes similar ice crystal patterns, and similar glassy states of the frozen matrix (uniformity of trapped moisture level, of glass transition temperature, or local glass-ice volumetric ratio, and of glass composition). These characteristics are desirable for achieving uniform product attributes throughout the volume, and reducing product loss. It is desirable to maintain similar freezing conditions independently of the freezing volume. Reproducibility of freezing in large and small samples permits process scale up and testing of small product samples under freezing conditions which may be later encountered in freezing of large volumes of biopharmaceutical products.
Cryopreservation and cryoprocessing is large volumes is especially desirable with respect to biopharmaceutical products. For instance, large scale processing may be useful in manufacturing of biopharmaceutical products. Such large scale processing is described in U.S. Pat. No. 5,964,100; and U.S. patent application Ser. Nos. 08/895,777; 08/895,782, now U.S. Pat. No. 6,196,296; Ser. Nos. 08/895,936, and 09/003,283, now U.S. Pat. No. 6,079,215. These documents, and all other documents cited to herein, are incorporated by reference as if reproduced fully herein. However, during development of processes for manufacturing the biopharmaceutical products, researchers may not have a lot of the biopharmaceutical product on hand. This makes process development and optimization difficult; there simply may not be enough product available at that stage to fill a vessel of tens or hundreds of liters in volume. Therefore, xe2x80x9cscaledownxe2x80x9d technologies are needed to simulate large scale, for example production scale, freezing and thawing (i.e. cryopreservation) in very small volumes, for example laboratory scale.
One solution is trying to simulate large scale cryopreservation or cryoprocessing using small volume containers. However, the inventor has uncovered a problem with freezing of small volumes comprising biopharmaceutical products. Under external cooling, a small volume of media comprising a biopharmaceutical product supercools first in a liquid form (reaches thermodynamic in equilibrium) and then rapidly solidifies. The temperature first drops to reach a supercooled state in a liquid (the supercooling occurs in a whole volume of liquid). Then, after the seeding crystals form, the small volume solidifies rapidly taking the heat of solidification. The small volume thus rapidly warms up to the solidification temperature (a short plateau at this level ensues followed by a temperature decline (the solidified small volume is cooled by external cooling).
During rapid solidification of the supercooled small volume, the entire small volume could rapidly solidify with ice crystals rapidly xe2x80x9cshootingxe2x80x9d into (and through) the solidifying volume. Typically, such crystals shoot from the coldest points on the small volume internal surface. Such rapid crystal growth may be detrimental to the biopharmaceutical product. This is particularly the case if the rapid growth produces very fine crystals, which results in a large biopharmaceutical product-ice interface area, etc. Furthermore, the supercooling effect is more pronounced in smaller volumes than in larger volumes. Therefore, such small volumes may not accurately model cryopreservation and cryoprocessing of larger volumes of biopharmaceuticals.
Accordingly, there is a need for methods and apparatus for cryopreservation and cryoprocessing of biopharmaceutical products that solve the deficiencies noted above.
In an aspect, the invention relates to a biopharmaceutical product cryopreservation system, for cryopreserving a biopharmaceutical product, comprising a cryopreservation compartment; a cryopreservation fluid located within the cryopreservation compartment; and a biopharmaceutical product cryopreservation vial located within the cryopreservation compartment and surrounded by the cryopreservation fluid, and the biopharmaceutical product cryopreservation vial comprising a body that comprises an oblong cross-section defining proximal and distal ends of the body, and at least one nucleating structure, coupled to a distal end of the body, and the body comprising a cryogenically stable material that is compatible with biopharmaceutical products.
In another aspect, the invention relates to a method of cryopreserving biopharmaceutical products comprising providing a cryopreservation compartment; locating a biopharmaceutical product cryopreservation vial within the cryopreservation compartment, wherein the biopharmaceutical product cryopreservation vial comprises a body that comprises an oblong cross-section defining proximal and distal ends of the body, and at least one nucleating structure, coupled to a distal end of the body, and the body comprising a cryogenically stable material that is compatible with biopharmaceutical products locating a cryopreservation fluid in a space outside of the cryopreservation vial but within the cryopreservation compartment; and removing heat from the cryopreservation compartment, thereby freezing the cryopreservation fluid.
In still another aspect, the invention relates to a biopharmaceutical product cryopreservation vial comprising a body that comprises an oblong cross-section defining proximal and distal ends of the body, at least one nucleating structure, coupled to a distal end of the body, and the body comprising a cryogenically stable material that is compatible with biopharmaceutical products.